Project Summary Radiotherapy is a crucial component of cancer care, employed in the treatment of over 50% of cancer patients. Patients undergoing image-guided radiotherapy routinely have inert radiotherapy biomaterials implanted into their tumors. The single function of these inert biomaterials is to ensure geometric accuracy during treatment. Given that these inert biomaterials already have such unfettered access to the tumor sub-volume, there is compelling rationale for upgrading those single function inert biomaterials to multifunctional or `smart' ones that can deliver additional therapeutic or treatment enhancing benefits. To this end, the central innovation and overall goal of this project is the development of Biomaterial drones for image- guided delivery of immunoadjuvants which can substantially boost both local and metastatic tumor kill with minimal systemic or overlapping toxicities. Our preliminary studies have already developed and tested the prototypes of our biomaterial drones, showing that they can indeed boost local and metastatic tumor cell kill. We will build on these preliminary results to optimize and establish capability for visualization and quantification of the 4 dimensional distribution of the immunoadjuvant drug payload. Major advantages of employing the drones for image-guided drug delivery include the following: 1) the drones can be employed at no additional inconvenience to cancer patients, since they would simply replace currently used inert biomaterials; 2) controlled in situ delivery of drugs using drones will allow direct delivery to the tumor, significantly minimizing systemic/overlapping toxicities, which are currently a critical barrier with competing approaches. 3) the sustained release and intra-tumor bio-distribution of drug payloads can be visualized and customized to enable superior therapeutic efficacy; 4) the drones design allows for loading of different therapeutic payloads. The specific aims of this project will focus on incorporating drug-loaded nanoparticles with inherent computed tomography (CT) and magnetic resonance imaging (MRI) contrast for visualization and quantification of distribution. Successful development of this technology could transform radiotherapy, allowing the use of the technology to combine radiotherapy and immunotherapy in one smart device, to boost treatment outcomes for patients with local or metastatic disease. Because, metastasis is responsible for over 90% of cancer deaths and suffering, many cancer patients would benefit from this new technology. The image guidance capability will also allow for treatment planning, and treatment response monitoring needed for facilitating clinical translation.